Camptothecin is a well-known alkaloid that was first isolated in 1966 from Camptotheca acuminate. Camptothecin shows strong cytotoxic activity and anti-tumor activity. Due to its poor water solubility (2.5 ug/mL), the first clinical trials in the early seventies were performed using CPT as the sodium salt of the hydroxycarboxylate form, with an open E-ring. However, severe and unpredictable side effects hindered further clinical development.
A renewed interest in CPT and CPT derivatives came with the elucidation of their mechanism of action, i.e. the inhibition of the nuclear enzyme topoisomerase I. It was also discovered that the lactone ring of CPT is necessary for specific interaction with topoisomerase I and selective antitumor activity. Several derivatives of CPT with improved solubility and lactone ring stability have been synthesized, including irinotecan and topotecan (which have been FDA approved for clinical use in the therapy of colorectal, ovarian and lung cancer), as well as SN-38, 9-Aminocamptothecin, 9-Nitrocamptothecin, GI-147211, Exatecan and Karenitecin. See Table 1. The clinical application of these drugs is, however, limited by their toxic, dose-related side effects, such as myelosuppression, gastrointestinal disorders and stomatitis.
Experience with these CPT derivatives suggests that the behavior of CPT derivatives in the presence of human serum albumin (HSA) is one of the determining factors of their clinical efficacy. The equilibrium concentration of active 9-Aminocamptothecin in blood is less than 0.5% due to preferential binding of the inactive 9-AC open-ring carboxy to HSA which shifts the blood equilibrium between the active, closed-ring 9-AC lactone and the inactive open-ring carboxy form toward the inactive, open-ring 9-AC carboxy form. CPT displays similar behavior. In contrast, the clinically important CPT derivative irinotecan and topotecan display enhanced lactone stability in the presence of HSA.
TABLE 1Well-known CPT derivatives. CompoundR2R3R4R5R6Camptothecin—H—H—H—H—HTopotecan—H—CH2N(CH3)2—OH—H—H Irinotecan—CH2CH3—H—H -HSN-38—CH2CH3—H—OH—H—H9-Aminocamptothecin—H—NH2—H—H—H9-Nitrocamptothecin—H—NO2—H—H—H GI-147211—H—OCH2CH2O— -HExatecan—CH3—F—H Karenitecin—H—CH2CH2Si(CH3)3—H—H—H
Furthermore, attempts have been made to selectively bind a biologically active, lactone form of a CPT derivative to HSA, in order to prevent HSA from preferentially binding and stabilizing the inactive carboxy form of the CPT derivative, thereby driving the lactone ring/open-ring carboxy blood equilibrium toward the active lactone ring form. However, these attempts have been only partially successful. For instance, in Z. M. Prijovich et al., Biochem. Pharm. 66 (2003): 1181-1187, 9-Aminocamptothecin glucuronide (9AGC) shows improved stability of the active lactone ring form in blood, reaching equilibrium in blood of about 20% lactone ring form and a blood half-life increased to about 50 minutes.
Accordingly, there is a clear and continuing need to create more soluble forms of CPT and analogs which remain substantially in their clinically effective lactone ring form in blood, and particularly in the presence of HSA.